The evidence linking cholesterol levels in the blood to vascular risk is now incontrovertible and the introduction of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor (or statin) therapy into clinical practice has now revolutionized the management of lipid disorders and silenced at a stroke the critics of cholesterol control as a means to vascular disease prevention. Statins were the first lipid-lowering agents, which, within a framework of a clinical trial, actually extended life by mechanisms that probably go beyond cholesterol alone. Their benefits are so impressive that some enthusiasts have been emboldened to write that they ‘are to atherosclerosis what penicillin was to infectious disease’. But is Nature as easily tamed as we might imagine? Some individuals show a modest or even poor response to statin therapy. The recent discovery of ezetimibe, a highly efficient and precise cholesterol absorption inhibitor, has proven to be a very effective cholesterol lowering alternative for them and combining statins with ezetimibe, thereby inhibiting cholesterol absorption and endogenous synthesis, takes us to realms of cholesterol lowering capability that could not have been dreamt of a decade ago.

Introduction

Among the plethora of risk factors which have been linked to coronary artery disease, hypercholesterolaemia appears to predominate. Populations with inherently low plasma cholesterol levels are able to withstand exposure to arterial hypertension and high levels of tobacco consumption without developing significant coronary atherosclerosis. However, when all three of these major coronary risk factors coincide, the risk of ischaemic heart disease increases multiplicatively. The lipid hypothesis, formulated approximately five decades ago and hotly debated for much of that time, speculated that reduction of plasma [or more specifically LDL (low-density lipoprotein)] cholesterol would lead to a fall in coronary heart disease morbidity and mortality. The introduction of three HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors or statins, in the late 1980s, provided the first effective tools for cholesterol lowering and set in motion a series of prevention trials whose results, once and for all, silenced the critics of cholesterol management as a means to reducing vascular risk. In fact, the benefits of these drugs were so impressive that some enthusiasts were emboldened to write that they ‘are to atherosclerosis what penicillin was to infectious disease’ [1]. However, the prime lesson that emerged from our use of antibiotics is that nature is not as easy to tame as we might imagine, and some are beginning to draw similar conclusions about statins. If these agents really lived up to expectation, they say, surely coronary events would have been eliminated in the published trials rather than ‘merely’ reduced by 30–50%. However, of course, no clinical trial can truly reflect the multifaceted biology of real life, and to eliminate a disease which is caused by the insidious tissue accumulation of cholesterol over a lifetime would undoubtedly require action over a longer time frame than is dictated by the exigencies of trial design.

Final confirmation of the lipid hypothesis: the merits of statins

Since their introduction into clinical practice 15 years ago, the statins have captured and expanded the cholesterol-lowering drug market. Until then, most lipid-lowering agents available were either modest in their effectiveness or associated with side effects so as to make them unacceptable to patients. The potency of the statins, although obviously beneficial in clinical terms, was in the first instance viewed by many with a degree of concern since they act primarily by targeting the rate-limiting step in the important metabolic cascade leading to cholesterol biosynthesis in hepatocytes. Their competitive inhibition of HMG CoA reductase eliminates the availability of cholesterol within these cells and, in consequence, upregulates LDL receptors on their cytoplasmic membrane. This leads to accelerated plasma clearance not only of LDL but also of its precursors VLDL (very low density lipoprotein) and IDL (intermediate density lipoprotein). Therefore, circulating LDL levels fall, partly because of an increase in catabolism and also because the availability of LDL precursors is curtailed.

The beneficial clinical outcomes of treatment with these agents have been impressively demonstrated in a number of recently published landmark outcome trials (Table 1). In the Scandinavian Simvastatin Survival Study [2], for example, total mortality in patients with a history of vascular disease was reduced by 30%, risk of coronary death by 42% and the risk of major coronary events by 34% in the statin-treated group. The West of Scotland Coronary Prevention Study [3] showed similar success in apparently healthy individuals, who had not had a heart attack. In CARE [4], myocardial infarction survivors with very average cholesterol levels also gained benefit. Pravastatin treatment here was associated with a 24% reduction in the risk of CHD (coronary heart disease) death or non-fatal MI (myocardial infarction), and the need for revascularization was reduced by 27%.

Table 1
Major coronary heart disease prevention studies with statins
Clinical trial Drug used No. of subjects Relative reduction in fatal or non-fatal MI (%) 
West of Scotland Coronary Prevention Study (WOSCOPS) Pravastatin 6595 31 
Cholesterol and Recurrent Events (CARE) Study Pravastatin 4159 24 
Scandinavian Simvastatin Survival Study (4S) Simvastatin 4444 34 
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Pravastatin 9014 23 
Air Force/Texas Coronary Atherosclerosis Prevention Study (AF/TEXCAPS) Lovastatin 6605 36* 
Heart Protection Study (HPS) Simvastatin 20536 24† 
AngloScandinavian Cardiac Outcomes Trial (ASCOT) Atorvastatin 10305 36 
The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Pravastatin 5804 19 
Clinical trial Drug used No. of subjects Relative reduction in fatal or non-fatal MI (%) 
West of Scotland Coronary Prevention Study (WOSCOPS) Pravastatin 6595 31 
Cholesterol and Recurrent Events (CARE) Study Pravastatin 4159 24 
Scandinavian Simvastatin Survival Study (4S) Simvastatin 4444 34 
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Pravastatin 9014 23 
Air Force/Texas Coronary Atherosclerosis Prevention Study (AF/TEXCAPS) Lovastatin 6605 36* 
Heart Protection Study (HPS) Simvastatin 20536 24† 
AngloScandinavian Cardiac Outcomes Trial (ASCOT) Atorvastatin 10305 36 
The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Pravastatin 5804 19 
*

Expanded endpoint of combined unstable angina, fatal and non-fatal MI and sudden cardiac death.

Major vascular events.

In the light of the findings of the above three studies and with the publication of more good news from the Australian/New Zealand LIPID Trial [5], from TexCAPS/AFCAPS [6], from the Heart Protection Study [7], from the Anglo-Scandinavian Trial [8] and from PROSPER [9], undertaken in elderly patients, we are moving towards the enviable position of being able to make evidence-based decisions on the use of lipid-lowering drugs. Central to this is the growing consensus that (i) the starting point for management should be CHD event risk and not simply serum cholesterol, (ii) absolute rather than relative risk reduction gives a better estimate of benefits of treatment and (iii) the best way to compare treatments is to calculate the number of patients who need to be treated to save one event. Viewed in this way, the distinction between primary and secondary preventions may eventually come to be regarded as somewhat artificial, with patients being classified instead as low, medium or high risk.

The mechanisms of action of statins

To appreciate the mechanisms by which the statins impact upon the plasma cholesterol level, we must first understand the regulation of cholesterol balance at a cellular level. The cholesterol economy of the cell is controlled by a family of recently discovered regulatory proteins, known as SREBPs (sterol-regulatory-element-binding proteins) [10]. These proteins control the transcription of the LDL receptor and at least six other key enzymic steps in the cholesterol biosynthetic pathway [11]. When the cholesterol level falls within the cell, the SREBPs are activated and they interact with the DNA of the cells, activating the transcription of various genes [10,12].

When we give statin therapy, we inhibit HMG CoA reductase, leading to a fall in the intracellular cholesterol concentration. As described above, this sets a train of events in motion, which ultimately enhances transcription of several proteins involved in cholesterol balance including, perhaps most importantly, upregulation of the LDL receptor. Transcription of HMG CoA reductase is also upregulated but this enzyme is not sufficiently increased to overcome the drug effect, i.e. there is more inhibition present than the excess enzyme produced.

The LDL receptor is a single transmembrane protein that binds apoB (apolipoprotein B) and apoE. The receptor therefore recognizes and interacts with particles containing these proteins but with different affinities, since apoE binds approx. ten times more effectively than apoB. In theory, then, a whole spectrum of lipoprotein particles found within the VLDL–LDL interval, which contains one or both of these proteins, could interact with, and be degraded by, the LDL receptor. Indeed, metabolic studies have now shown that statin therapy is not simply associated with an increased clearance of LDL [13] but also of VLDL and IDL [14].

The statins and plasma LDL cholesterol

Plasma LDL-cholesterol reductions achieved with statin therapy appear to be independent of the baseline lipid phenotype. That said, it must also be appreciated that between statins there are marked differences in cholesterol-lowering effectiveness and wide interindividual variation in response to the same dose of any one statin. For example, an early study of simvastatin at 40 mg/day for 3 months produced approx. a decrement in LDL-cholesterol of over 60% to an increment of almost 10% [15].

There are many small studies defining the biochemical effectiveness of the statins either individually or in comparison with each other. However, any tabular comparison of the cholesterol-lowering effects of the statins inevitably raises more questions than it answers, as small studies are often included alongside large-scale studies, results achieved in normal practice are compared with the results achieved in a controlled clinical trial setting and different doses are compared. What is obvious from studies with all the statins is that the dose–response is not a simple linear one. Doubling the dose of any statin does not double the percentage cholesterol lowering. Indeed, as a rule of thumb, each time the dose is doubled an approx. 6% further LDL-cholesterol reduction is achieved.

Although there are clear pharmacological differences between the statins in terms of the cholesterol reductions seen with equivalent doses, it is probably true to say that by adjusting the doses accordingly, all statins are capable of producing equivalent reductions in LDL-cholesterol. What is not clear from studies completed so far is whether such dose adjustments will be equally free from side effects for each statin or whether therapy with all statins, irrespective of their potency in lowering LDL-cholesterol, will have the same effect on clinical events.

Statins and combination therapy

The consistency and potency of the HMG CoA reductase inhibitors and their proven ability to reduce the risk of cardiovascular disease has revolutionized, within the space of a decade, the practice of preventive cardiology. However, the expectations of guideline writers have also been sharpened and, in consequence, clinicians are being encouraged to aim for progressively lower cholesterol targets. It is not surprising therefore that a gap has begun to appear between the lipid goals mandated by the guidelines and the reductions achieved in clinical practice. A number of factors are clearly responsible for this development. First-generation statins like lovastatin, pravastatin and simvastatin, considered earlier to be revolutionary in terms of their potency, are often stretched to their limits and beyond by the lipid reductions required to achieve the latest guideline targets; and the appearance of side effects such as myopathy and liver function abnormalities when statins are titrated upwards has raised concerns in the minds of patients and physicians, which may prevent full use of the available statin doses.

We also need to consider another important mechanistic issue. Corporeal cholesterol homoeostasis depends on the balance between endogenous cholesterol production (principally in the liver) and intestinal absorption of the sterol from the diet and the enterohepatic circulation (Figure 1). Suppression of endogenous cholesterol production by statins does nothing to inhibit the absorption of exogenous sterol and can therefore only be expected to be partially effective in reducing plasma cholesterol levels. What is clearly required is simultaneous inhibition of endogenous synthesis and exogenous sterol absorption. Statins effectively provide the former while the recently identified ezetimibe is uniquely able to deliver the latter.

Cholesterol balance in man

Figure 1
Cholesterol balance in man

Each day we ingest approx. 300 mg of cholesterol in our diet which, in the small intestine, mixes with approx. 900 mg of endogenously produced sterol. During equilibrium, therefore, about 1200 mg of sterol is lost daily into the faeces. The rate-limiting enzyme for endogenous cholesterol production is HMG COA, the target enzyme for statin therapy. Statins therefore inhibit cholesterol production but have little or no effect on its absorption. Cholesterol is transported throughout the bloodstream in plasma lipoproteins. VLDLs and LDLs are responsible for its delivery from liver to peripheral tissues, whereas HDL is the primary vehicle in the process of reverse cholesterol transport.

Figure 1
Cholesterol balance in man

Each day we ingest approx. 300 mg of cholesterol in our diet which, in the small intestine, mixes with approx. 900 mg of endogenously produced sterol. During equilibrium, therefore, about 1200 mg of sterol is lost daily into the faeces. The rate-limiting enzyme for endogenous cholesterol production is HMG COA, the target enzyme for statin therapy. Statins therefore inhibit cholesterol production but have little or no effect on its absorption. Cholesterol is transported throughout the bloodstream in plasma lipoproteins. VLDLs and LDLs are responsible for its delivery from liver to peripheral tissues, whereas HDL is the primary vehicle in the process of reverse cholesterol transport.

Ezetimibe – the ideal complement to statin therapy

Ezetimibe (Figure 2) is the first of a new class of cholesterol-lowering compounds, which acts at the brush border of the small intestinal enterocytes to inhibit selectively the absorption of cholesterol and closely related plant sterols like β-sitosterol. It is a low-molecular-mass compound (409.4 Da) and virtually water-insoluble. Following its ingestion, preliminary conjugation in the small intestine [16] to an active water soluble phenolic glucuronide permits its partial absorption and within 30 min, 90% of the ezetimibe found in the circulation is glucuronidated.

Structure of ezetimibe (SCH 58235)

Figure 2
Structure of ezetimibe (SCH 58235)

Ezetimibe is a potent and specific inhibitor of dietary and biliary cholesterol absorption.

Figure 2
Structure of ezetimibe (SCH 58235)

Ezetimibe is a potent and specific inhibitor of dietary and biliary cholesterol absorption.

Subsequent cyclic oscillations in the plasma concentration of both the free drug and a variety of glucuronide conjugates at approximately 4 h intervals over as long a time interval as 10 days [17] suggest that they are subject to a process of enterohepatic recirculation that effectively redelivers the drug time and again to its site of action in the small intestine. Although ezetimibe is regarded as a systemic drug and can be detected in the systemic circulation, its largely enterohepatic containment limits the exposure of peripheral tissues and minimizes the potential for side effects. Predictably, both the ezetimibe and glucuronide, which appear in the systemic circulation, are highly (>90%) protein-bound and have a long half-life (∼22 h). Almost 70% of the ingested drug is excreted unchanged in the faeces, and glucuronide is the major component found in the urine [∼10% of the ingested dose; Zetia (ezetimibe) product information, North Wales, PA, U.S.A. Merck/Schering-Plough, October 2002].

The mechanism(s) of action of ezetimibe

Corporeal cholesterol homoeostasis (Figure 1) depends on the balance [19,20] between endogenous cholesterol production (principally in the liver) and the intestinal absorption of the exogenous sterol from the diet. Before statins (which suppress hepatic cholesterol synthesis) became available, strategies designed to lower the whole body cholesterol burden were focused primarily on limiting dietary cholesterol intake. However, this strategy proved to be largely ineffective since lowering dietary cholesterol intake by 100 mg/day decreased total and LDL cholesterol in the circulation by only 0.065 and 0.05 mmol/l respectively and, disconcertingly, also lowered HDL (high-density lipoprotein) cholesterol by 0.01 mmol/l [21,22]. Consequently, the ratio of LDLc/HDLc (an important measure of the atherogenicity of the circulating lipoproteins) remained unchanged. It transpired that a number of factors contributed to this unspectacular response to dietary cholesterol limitation, but high on the list was the relatively low contribution that dietary cholesterol makes each day to the flux of sterol through the intestinal lumen. In adults consuming a typical Western diet, only about one-third to one-quarter of the daily 1000–1500 mg of cholesterol which passes through the gut is actually derived from dietary sources. The remainder, fabricated mainly in the liver, is secreted directly into the bile. Consequently, a much more effective method of limiting exogenous sterol assimilation would be through inhibition of intestinal cholesterol absorption.

The discovery of ezetimibe and its introduction into clinical practice has reawakened interest in the search for the detailed mechanism(s) of cholesterol absorption. Following administration, the drug and its glucuronide metabolite impair the intestinal reabsorption of dietary and hepatic biliary cholesterol [23,24]; and studies in rats have established that 3H-labelled ezetimibe glucuronide injected directly into the bile duct becomes localized on the luminal brush border of upper small intestinal enterocytes [25] and inhibits cholesterol assimilation by these cells without affecting either hepatic or intestinal cholesterol synthesis [23]. Despite this unquestionable evidence of specific and selective inhibition of cholesterol by ezetimibe and its glucuronides and even with the fabrication of novel labelled ezetimibe analogues [24,25] and their deployment in a number of ingenious studies [24,2628], the details of the cholesterol absorptive process remain elusive. A recent publication from Altmann et al. [29] may change all of this. Their study set out to identify the genes involved in sterol absorption using a genomics–bioinformatics approach. Approximately 16500 expressed DNA sequences, isolated from rat jejunal mucosal DNA, were combined with all publicly available rat genomic material and cross-compared with mouse and human DNA banks. Sequences containing the features of a membrane cholesterol transporter were identified in the material from all three species. Only one credible candidate gene emerged from the analysis – the rat homologue of NPC1L1 (Niemann–Pick C1-like protein 1).

NPC1L1 has approx. 50% amino acid sequence homology with NPC1, a gene that is defective in the Niemann–Pick type C cholesterol storage disease and it normally functions in intracellular cholesterol trafficking. Whereas NPC1 is widely expressed throughout the tissues of the body, its homologue NPC1L1 is selectively enriched in the gastrointestinal tract, an observation which favours its candidacy in intestinal cholesterol absorption. Support for this proposal came from a gene-modified mouse model. NPC1L1 knockout mice were impaired in their ability to absorb cholesterol even when their diet was enriched in the sterol, suggesting that NPC1L1 is critical for cholesterol uptake across jejunal enterocyte membranes. The complete insensitivity of NPC1L1-deficient mice to ezetimibe suggests that NPC1L1 or a closely associated protein may be the molecular target for this drug.

Practical considerations – statins and ezetimibe in combination

The good safety profile of ezetimibe when administered in monotherapy and its complementary suppression of intestinal cholesterol absorption are well matched to the role of statins in inhibiting hepatic cholesterol synthesis. Combination therapy with ezetimibe and statins would therefore probably bring recalcitrant patients to lipid targets without increasing their risk of side effects. In consequence, substantial effort has been expended to establish the efficacy and safety of this lipid-lowering drug combination. First and foremost was the need to establish in small pilot studies, the safety of ezetimibe–statin combinations in pharmacokinetic terms [30].

The promise of these early studies was realized in a formal series of integrated investigations employing lovastatin, pravastatin, simvastatin and atorvastatin. Almost 2400 subjects were enrolled in this project, the commonality of whose design allowed for integration of the analysis of the entire database [3134].

The findings for each of the four statin arms were remarkably concordant. Ezetimibe (10 mg) added to statin at every dose level produced a further lowering in LDLc between 12 and 16%. Triglyceride levels also decreased and there was a small but significant rise in HDL cholesterol. Interestingly, when high-sensitivity C-reactive protein levels were measured in the simvastatin arms of the trials [35], addition of ezetimibe to the statin produced a further significant decrement in C-reactive protein over that observed with the statin alone. Although the clinical significance of this is unclear, it is tempting to speculate that the combination may produce an added anti-inflammatory benefit over and above that seen with the statin, possibly because of the additional improvements in the lipid profile.

As a consequence of dual inhibition of cholesterol absorption in the gut and synthesis in the liver, the combination of ezetimibe with a statin therefore offers highly efficacious lipid lowering without apparent safety penalty. Ezetimibe (10 mg) plus the lowest dose of statin produce an equivalent LDL cholesterol reduction as the highest dose of statin monotherapy. This combination therefore broadens the treatment strategy for clinicians concerned over the potential side effects of high-dose statins.

Conclusions

Statins have revolutionized the management of hypercholesterolaemia and, rightly, dominate the lipid-lowering drug field. However, the recent global launch of the ‘superstatin’ rosuvastatin means that the market for this class of compounds is becoming crowded. The biggest threats to the statin market are their imminent loss of patent protection and the subliminal misgivings about their safety in combination with the other drugs such as gemfibrozil following the prominent withdrawal of cerivastatin in 2001. Such thinking, coupled with the growing acceptance of the safety of ezetimibe–statin combinations is opening the door to the development of a single ezetimibe–simvastatin formulation. Such a pill, if aggressively priced in relation to atorvastatin and rosuvastatin, would permit Merck/Schering Plough, the owners of simvastatin and ezetimibe, to extend the simvastatin franchise for years beyond its patent expiry, currently in most of Europe and scheduled for 2005 in the United States. Monotherapy with ezetimibe is likely to take only a small piece of the lipid lowering drug market. However, the additional potency and putative safety of the ezetimibe–statin combination pill will probably see progressive market penetration with predicted annual sales of more than three billion US$s by the year 2011.

Research Colloquia: Research Colloquia at BioScience2004, held at SECC Glasgow, U.K., 18–22 July 2004. Edited by M. Bouvier (Montreal, Canada), G. Milligan (Glasgow, U.K.), V. O'Donnell (Cardiff, U.K.), M. Brand (MRC-Dunn Human Nutrition Unit, Cambridge, U.K.), M. Schweizer (Heriot-Watt University, Edinburgh, U.K.), R. Insall (Birmingham, U.K.), A. Ridley (Ludwig Institute for Cancer Research, London, U.K.) and M. Sutcliffe (Leicester, U.K.). The first eight papers featured in this Section were presented as a part of the GPCR Regulation and Signalling Research Colloquium, incorporating the GPCR–Ion Channel Interactions Pfizer-Sponsored Research Colloquium.

Abbreviations

     
  • apo B

    apolipoprotein B

  •  
  • HDL

    high-density lipoprotein

  •  
  • HMG

    3-hydroxy-3-methylglutaryl

  •  
  • IDL

    intermediate density lipoprotein

  •  
  • LDL

    low-density lipoprotein

  •  
  • MI

    myocardial infarction

  •  
  • NPC1L1

    Niemann–Pick C1-like protein 1

  •  
  • SREBP

    sterol-regulatory-element-binding protein

  •  
  • VLDL

    very-low-density lipoprotein

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